Background The fraction of exhaled nitric oxide (Fᴇɴᴏ) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Fᴇɴᴏ values might help to define biological mechanisms related to specific asthma phenotypes.

Objective We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma.

Methods Fᴇɴᴏ values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with Fᴇɴᴏ values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110).

Results We identified 3 SNPs associated with Fᴇɴᴏ values: rs3751972 in LYR motif containing 9 (LYRM9; P = 1.97 × 10−10) and rs944722 in inducible nitric oxide synthase 2 (NOS2; P = 1.28 × 10−9), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB; P = 1.88 × 10−8) at 17q12-q21. We found a cis expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma.

Conclusion This study identified 3 variants associated with Fᴇɴᴏ values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of Fᴇɴᴏ values. This study highlights that both shared and distinct genetic factors affect Fᴇɴᴏ values and childhood asthma.